The klotho gene is known to play a role in suppressing several different aging phenotypes, based on studies in the klotho mutant mouse. Mice homozygous for defects in the klotho gene exhibit a syndrome that closely resembles human aging, including atherosclerosis, osteoporosis, emphysema, infertility and skin atrophy. We hypothesize that specific klotho variants found in mice associated with increased longevity may operate in humans. We have genotyped the entire BLSA and InChianti populations for the KL-VS allele. Data analysis is underway to search for correlations between specific allelic variants and phenotypes examined in the BLSA and InChianti studies. In the last reporteing period, we expanded the analysis to include polymorphisms in the LMNA gene in both the BLSA and InCHIANTI populations. We completed analysis of the relationship between the Klotho VS polymorphism in the BLSA and found it to be associated with insulin resistance (abnormal 2h glucose tollerance test) in men but not in women. Interestingly, both in men and in women, the VS+ polymorphism was not associated with fasting insulin. The data on the Klotho polymorphism in the InCHIANTI study have not been analyzed. A manuscript has been submitted and we are conducting further analyses aimed at demonstrating that while Klotho affect glucose metabolism during an OGTT test, perhaps by modulating insulin resistance, it does not affect glucose metabolism at rest which may explain the negative results reported by other studies.